The complement system provides a first line of host defense against invading pathogens. Complement also plays a pathogenic role in human inflammatory diseases. Activation of the complement system occurs via three different pathways, the classical pathway (CP), the lectin pathway (LP) and the alternative pathway (AP). The CP is initiated by antigen-antibody binding. The LP is triggered when mannose-binding lectins (MBL) interact with surface sugar molecules on microorganisms. Activation of both pathways leads to the assembly of the CP C3 convertase C4b2a, although direct cleavage of C3 by MBL-associated serine proteases can also occur. The AP is a self-amplification loop driven by the AP C3 convertase, C3bBb. AP activation can occur secondary to CP or LP activation, or is initiated independently. In the latter case, a low level spontaneous C3 ‘tick-over’ generates the initial C3bBb, which rapidly propagates the AP in the absence of adequate regulation. Thus, it is generally assumed that AP activation on non-self surfaces with no or insufficient negative regulation is considered a default process, whereas autologous cells typically avoid this outcome with the help of multiple membrane-bound and fluid phase complement inhibitory proteins. Under certain conditions, altered, damaged or stressed autologous cells and tissues can also activate AP and cause inflammatory injury.
In contrast to the existence of numerous inhibitory proteins, the plasma protein properdin is the only known positive regulator of the complement activation cascade. Properdin is a plasma glycoprotein of approximately 53 kDa with an estimated blood concentration of 5-10 μg/ml. It exists mostly as dimers, trimers and tetramers in a fixed ratio, in a head-to-tail conformation. The currently held view on properdin function is that it facilitates AP activation by extending the half-life of the nascent C3bBb convertase. According to this view, properdin plays a facilitating, but not essential, role in AP activation. Since activation of the CP and the LP will invariably trigger the AP amplification loop, it is expected that properdin will also indirectly promote CP- and LP-mediated complement activation. Thus, based on the prevailing knowledge prior to this invention, one may not regard properdin as an attractive anti-complement therapeutic target because it lacks specificity and is not indispensable for complement activation.
While all three pathways of complement activation help the host in fighting microbial infection, recent studies have shown that complement-mediated pathology in humans, such as age-related macular degeneration, atypical hemolytic uremic syndrome, paroxysmal nocturnal hemoglobinuria (PNH), rheumatoid arthritis, allergic asthma and ischemia reperfusion injury, is mainly mediated by the AP. Thus, there remains a need in the art for anti-complement compositions and methods of treating human inflammatory diseases by selectively inhibiting the AP while leaving intact the CP and the LP to fight pathogens and to protect the host from infection. The current invention fulfills this need.